The long-term goal of this proposal is to identify links between specific environmental exposures and/or specific gene alleles, and multiple sclerosis onset and progression. A cohort of 1294 pairs of North American twins affected by multiple sclerosis was assembled from 1980-92, detailed medical records, exposure and disability information were gathered independently from affected and unaffected individuals, and follow-up for new diagnoses and new records has subsequently proceeded. An additional set of 195 pairs of affected California native resident twins has been identified within a cohort of 41,000 twins participating in a population-based registry. The up-date on all cases will be completed, diagnoses will be systematically validated using the additional records, and age-specific disability information will be gathered. Blood specimens from both members of each pair and from specific family members as controls will be collected. The affected twins will be compared to their unaffected co-twins with respect to historical evidence of infection and other exposures and characteristics such as reproductive evidences of endogenous estrogen production. Cases will be compared to both co-twins and family member controls with respect to serological evidence of past infection with Chlamydia pneumoniae and members of the herpes virus family. We will compare cases to relatives with respect to the prevalence of alleles at the HLA (DR) locus as well as at various other candidate loci, found by genome-wide screening or that affect immune competence, myelin basic protein, and other pertinent functions. Within the set of cases only, both environmental and genetic factors will be assessed as determinants of age at onset and age-specific progression. If links to both acquired exposure and genome are identified, given adequate power, specific gene- environment interactions will be assessed. Analyses for both etiology and progression will consist of logistic regression and sub-analyses stratified on gender, zygosity, and HLA (DR) status. Additional descriptive evidence of environmental etiology will also be sought.